Dr. David Margolin graduated magna cum laude from Harvard College, and obtained his medical and doctoral degrees from the University of Pennsylvania. Since completing a neurology residency at the Massachusetts General Hospital (MGH), he has been a postdoctoral fellow in the Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center (BIDMC), supported by a fellowship from the Harvard AIDS Institute. At the same time, he served as coordinator of the HIV Neurology services at MGH where he will become an Instructor in Neurology of the Harvard Medical School. He is committed to a full-time career as a clinical scientist. While serum antibodies to HIV-1 have been intensively studied, important questions remain regarding the clonal generation of HIV-1 specific B lymphocytes. In studies employing the SHIV/macaque model, Dr. Margolin will identify B cells producing HIV-1 specific antibodies in situ and clone the genes encoding their immunoglobulins. Localization of virus- specific B cells will be combined with an analysis of the phenotype and cytokine profile of cells that constitute the B cell microenvironment, providing important insights into cellular mechanisms that generate a humoral immune response to the AIDS virus. Comparison of lymphoid tissues obtained during primary SHIV infection and at later timepoints will provide clues to the molecular evolution of HIV-1-specific antibodies. Combined histopathologic analyses and sequencing of immunoglobulins will elucidate important aspects of AIDS immunopathogenesis, defining the clonal dynamics and pathophysiology of follicular hyperplasia, the differential regulation of antibody responses to Env and Gag proteins, and clonal dominance among virus- specific B cells. Dr. Margolin's research and maturation as an investigator will be facilitated by his association with Dr. Normal Letvin, Chief, Division of Viral Pathogenesis at BIDMC and Dr. Anne B. Young, Chief, Neurology at MGH. Dr. Letvin and Dr. Young are fully committed to Dr. Margolin's development as an independent investigator. A committee of distinguished scientists to oversee Dr. Margolin's progress will include two AIDS researchers and a neuroimmunologist.